R. M. Pauli, M.D., Ph.D.

This study attempts to simultaneously assess two variables — postterm pregnancy and intrauterine growth retardation. It asks a very reasonable question: Do risks of stillbirth increase solely based on postdates or is the well known increase the result of some factor that also results in intrauterine growth restriction? This is an exceedingly well designed, population based study with data derived from the National Swedish Medical Birth Registry. Virtually all pregnancies were ascertained for 1987-1992. Only those with good dating by early ultrasound were included. About 180,000 pregnancies of 40 weeks gestation and beyond were analyzed. Odds ratios for intrauterine deaths increased substantially with increasing gestational age — 1.0 at 40 weeks, 1.5 at 41 weeks, 1.8 at 42 weeks and 2.9 at 43 weeks (with no significant difference for neonatal deaths). However, much of this is attributable to pregnancies with intrauterine growth retardation (defined here very selectively as those with weight below 2 standard deviations). In fact the odds ratios for those that are both postdates and growth restricted ranged from 7 to 10 (as well as more modest risks for neonatal death). Removing all those with growth retardation dropped the odds ratios for postdates only to between 1.2 and 1.5. Hence, both postdates and intrauterine growth retardation independently increase risk of intrauterine death. When both are present risk is very high, while absent growth problems, postdates per se carries exceedingly modest risk. This would suggest, in addition to what many now consider routine monitoring of postdates pregnancies (e.g. twice weekly biophysical profile, ultrasound for amniotic fluid volume, careful followup in general) that not only should growth restriction be sought but, if found, perhaps those babies should be delivered without such a period of watchful waiting.

Impaired growth and risk of fetal death: Is the tenth percentile the appropriate standard? Seeds JW, Peng T. Am j obstet gynecol 178:658-669,1998.

Intrauterine growth retardation is associated with increased risks of perinatal mortality, neonatal morbidity, infant death and so forth. Different boundaries have been used to define intrauterine growth retardation (also referred to as intrauterine growth restriction, small for gestational age etc.). Generally in this country it is defined as being less than 10th percentile for weight. This study asked whether the 10th percentile is an appropriate cutoff. It simply linked birth certificates, death certificates and fetal death reports. There was no extrinsic confirmation of the data contained on these records nor was there any assessment of underascertainment of fetal deaths through fetal death reports. How execrable is the resultant data is reflected in the fact that only 1 in 1,000 had reported malformations and only 1 in 400 was reported as stillborn! So, while the authors felt that they could draw conclusions from this data, the defects are so obvious and glaring that I can hardly believe that this was published. Don’t read it. Don’t worry about the conclusions.

Intertwin disparity in fetal size in monochorionic and dichorionic pregnancies. Sebire NJ, D’Ercole C. Soares W. Nayar R, Nicolaides KH. Obstet gynecol 91:82-85, 1998.

The hidden mortality of monochorionic twin pregnancies. Sebire NJ, Snijder RJM, Hughes K, Sepulveda W, Nicolaides KH. Br j obstet gynecol 104:1203-1207, 1997.

These two articles are based upon data from the same large series of pregnancies in which ultrasound was carried out uniformly between 10 and 14 weeks. From that very large series, these studies focus on twin pregnancies. The first demonstrates that size disparity at that time in pregnancy is the same for monochorionic (and hence monozygotic) and dichorionic (85% dizygotic) twins. The only factors associated with such early size disparity included chromosomal abnormalities in dichorionic pregnancies and subsequent fetal death in dichorionic pregnancies. This may initially seem counter-intuitive since the most frequent causes of marked size disparity, such as twin-twin transfusions only occur if the placenta is monochorionic. However, the size-associated problems related both to twin-twin transfusion and placental adversity only arise considerably later in pregnancy and so would go undetected by early ultrasound. Early ultrasound, then, is of little use in assessing for such complications. The second study, again following pregnancies in which ultrasound was completed between 10 and 14 weeks, tracked 102 monochorionic twin pairs. Of the 204 fetuses, 25 (12%) died prior to 24 weeks gestation and 5 more (2.8%) suffered perinatal deaths. Rearranging the data to conform to the U.S. definition of stillbirth, 17 infants died in utero at 20 or more weeks gestation (8.3%, compared to around 2% in dichorionic twins), or about ten times the rate in singletons. Of these, 10 deaths were attributable to twin-twin transfusions.

Interleukin-10 attenuates experimental fetal growth restriction and demise. Rivera DL, Olister SM, Liu X, Thompson JH, Zhang X-J, Pennline K, Azuero R, Clark DA, Miller MJS. FASEB j 12:189-197, 1998.

This is an article that, I would guess, has crossed very few of your desks. Yet, it is sometimes exciting to try to read the future of perinatal care. There are many fetal deaths for which no explanation can be found. Here is an example of a possible new method of treatment that could substantially change the assumption that these fetal deaths of apparent unknown cause are unpreventable. Fetal death, intrauterine growth retardation and premature labor are all often associated with signs of inflammation (without overt infection). This group developed an animal model to assess whether that inflammation could be reduced and, if so, whether pregnancy outcome was thereby changed, too. Using rats, they administered low dose endotoxin to elicit an inflammatory response. This resulted in 43% of fetuses dying in utero (as well as a substantial increase in intrauterine growth retardation). Treatment with interleukin-10 (which normally is expressed at high levels during pregnancy) markedly reduced the death rate, to 22% (and also decreased the severity of intrauterine growth retardation). The mechanism of this beneficial effect was also investigated. Interleukin-10 appears to decrease two paths that lead to increased cell death — cytokine expression and nitric oxide mediated cell death. These results suggest that cell death (perhaps placental) and inflammation might be a mechanism causing intrauterine death and that an agent such as interleukin-10 might be useful in instances of fetal distress, growth retardation, in prevention of stillbirth recurrence etc. Venture capitalists take note, Schering-Plough helped sponsor this study. On the one hand, remember the name — it might be a central pharmacologic agent for the future. On the other, like any experimental study, this might prove to be nothing.

Outcomes of pregnancy in insulin dependent diabetic women: results of a five year population cohort study. Casson IF, Clarke CA, Howard CV, McKendrick O, Pennycook S, Pharoah POD, Platt MJ, Stanisstreet M, van Velszen D, Walkinshaw S. BMJ 315:275-278, 1997.

Historically, maternal insulin dependent diabetes mellitus has been associated with markedly excessive risks for intrauterine death, fetal malformations and neonatal sequelae. Recent studies, particularly the Diabetes Control and Complications Trial, have suggested that with rigorous control during pregnancy most or all of those risks can be reduced to near background level (with some persisting increase in perinatal death rate). However, the women who participate in such trials are self-selected, exceedingly highly motivated and, for the most part nonrepre-sentative of the entire population of women with diabetes with respect to intelligence, socio-economic status, understanding of their disease etc. So, there is some value in asking about recent ‘real-world’ experience. This article assesses 462 pregnancies followed in 10 hospitals in England between 1990 and 1994. The overall outcomes were not nearly so optimistic as one might hope. Of 462 pregnancies, 24 were terminated, including 9 with recognized major malformations. In addition, 78 resulted in spontaneous abortions and 9 were stillborn. Note that this intrauterine death rate is about 5 times the expected for these hospitals. Overall, malformations were ten times as likely as in nondiabetic pregnancies. Finally, on average, live birthweights were 1.3 standard deviations above the mean for gestational age. So, with ‘reasonable’ motivation and control and using methods of monitoring currently available, still only about 70% of pregnancies resulted in a healthy baby; 2-3% will be stillborn.

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